Both genetic and environmental factors play a major role in aging and the quality of life in the elderly. This project entitled "Energy Metabolism and Oxidative Stress in Aging" is part of a multi-disciplinary, multi-institutional approach to provide the fundamental knowledge that will allow the creation of preventive and compensatory interventions to improve the health of the aging population. Calorie restriction from birth or during adult life is known to prolong life in rodents and lower species alike. Calorie restriction may confer increased longevity by lowering metabolic rate and therefore reducing the oxidative damage caused by deleterious byproducts of energy metabolism called reactive oxygen species (ROS). In this project we will test whether healthy nonagenarians have a relatively low metabolic rate when compared to middle aged and young individuals and whether the low metabolic rate is associated with low levels of oxidative stress as measured by DNA damage, lipid peroxidation and protein carbonylation. Since very little is known about physical activity in very old people, we will measure it using state-of-the-art methods, i.e. doubly labeled water. The level of physical activity will be compared to the results of physical functionality assessed in Project 4 of this application with the hypothesis that these 2 parameters will be positively correlated. We will also test whether nonagenarians have unusually low levels of markers for cardiovascular disease and insulin resistance. Finally, we will determine whether nonagenarians have a particular pattern of serum proteins compared to younger groups of subjects. In this revised application, we now provide preliminary data about our ability to measure oxidative DNA damage (relationship between age and DNA oxidative damage) and proteomics (composite gel comparing the serum protein of a 92 to a 45 year old female) in old and younger subjects. Data from Project 3 will be compared to data from Projects 1, 2, 4 and 5, including genetic results, expression of genes involved in carbohydrate metabolism and stress resistance, physical functionality and cognitive functionality. Subjects will be recruited, screened and enrolled in the study over the 4 first years, and the fifth year will be used to analyze the data and write up the results.